The long-term objective of this Bioengineering Research Partnership proposal from the University of Pennsylvania (Penn) and Brigham and Women's Hospital (BWH) is to develop an optimized collimation system for preclinical cardiac imaging that offers higher performance than that of commercially available preclinical systems at a cost that is a small fraction of the price of stand-alone commercial systems~ we estimate this cost at about $97k (~15%). We will develop a complete preclinical conversion package for clinical triple-head scanners that users may already have or that can be leased from our corporate partner for about $40k/year, including the cost of maintenance. This cost is less than the maintenance cost alone for commercially available stand-alone preclinical scanners, without even considering the purchase or lease price of the machines. The proposed collimator tube will be fabricated from tungsten-polymer using rapid-prototyping and casting techniques~ the initial version of this tube will contain a large number (~150-200) of very high-density platinum- iridium alloy pinhole inserts optimized for preclinical cardiac imaging and will consist of two sections: (i) a high- resolution section providing reconstructed resolution of 0.5 mm or better and a sensitivity of about 0.5% over a field of view (FOV) appropriate for cardiac imaging, and (ii) a scout-imaging section with a larger FOV, but more modest resolution. The sections can be rapidly changed by robotically translating the tube axially. This combination will not only provide a scout image for accurate positioning of the heart, but will also acquire information about the activity distribution surrounding the heart tha would otherwise be truncated if using the high-resolution section alone. Future versions of the tube may contain additional sections to allow multi-stage imaging. One of the key concepts of this proposal is the use of square-aperture inserts to provide efficient tiling of projections fro multiple pinholes, as well as higher sensitivity than that of circular apertures for the same resolution. Because rapid-prototyping molds will be used for tube fabrication, these inserts will all be positioned and oriented to yield optimal imaging performance. Customized phantoms -- designed specifically for preclinical cardiac imaging tasks and also fabricated using rapid-prototyping techniques -- will be used for initial performance evaluations at both Penn and BWH, as well as for comparisons with other preclinical imaging systems. The new systems' utility for advancing cardiovascular science, as well as their full range of functionalit, will then be thoroughly demonstrated through multidisciplinary research studies with our biomedical collaborators~ these projects will provide essential feedback to the principal investigators for optimizing acquisition protocols, while also addressing important and timely topics in cardiovascular science, related to imaging of (i) perfusion with both sestamibi and a novel tracer in normal myocardium~ (ii) perfusion with both tracers in ischemic myocardium~ (iii)~ fatty-acid metabolism~ (iv) chemotherapy-induced cardiotoxicity~ (v) monocyte homing to atheroplaques~ and (vi) nanoparticles and calcifications in atherosclerosis.